Copper-Catalyzed Intramolecular Olefinic C(sp2)–H Amidation for the Synthesis of γ-Alkylidene-γ-lactams

Herein, we report the copper-catalyzed dehydrogenative C(sp2)–N bond formation of 4-pentenamides via nitrogen-centered radicals. This reaction provides a straightforward and efficient preparation method for γ-alkylidene-γ-lactams. Notably, we could controllably synthesize α,β-unsaturated- or α,β-saturated-γ-alkylidene-γ-lactams depending on the reaction conditions.

With the optimized reaction conditions in hand, we next investigated the substrate scope for the 5-alkylidene-3-pyrrolin-2-one synthesis using tBuOOtBu as the oxidant (Scheme 2).First, we explored the scope of diarylethylene acceptors.Substrates possessing functional groups such as methyl and methoxy groups, and halogen atoms on both benzene rings afforded the desired products in moderate to high yields (2b-f).The cyclization of the substrates with tricyclic scaffolds proceeded to furnish the corresponding products (2g and 2h).Subsequently, we investigated substitution in the aniline ring and observed that the process afforded good-to-high amounts of cyclized products, regardless of the electronic properties of the aniline ring (2i-r).With the optimized reaction conditions in hand, we next investigated the substrate scope for the 5-alkylidene-3-pyrrolin-2-one synthesis using tBuOOtBu as the oxidant (Scheme 2).First, we explored the scope of diarylethylene acceptors.Substrates possessing functional groups such as methyl and methoxy groups, and halogen atoms on both benzene rings afforded the desired products in moderate to high yields (2b-f).The cyclization of the substrates with tricyclic scaffolds proceeded to furnish the corresponding products (2g and 2h).Subsequently, we investigated substitution in the aniline ring and observed that the process afforded good-to-high amounts of cyclized products, regardless of the electronic properties of the aniline ring (2i-r).
Having studied the scope of the reaction, we next conducted experiments to obtain an insight into the reaction mechanism (Scheme 4).First, under both optimized conditions, the reactions were performed in the presence of the radical scavengers 2,6-di-tert-butyl-4methylphenol (BHT) or hydroquinone, which led to a significant decrease in the yield of 2a (condition A) or 3a (condition B) (Scheme 4a).These results suggest that the reactions proceeded via radical processes.Next, to investigate the possibility of saturated-r-lactam 3a acting as an intermediate for 2a, the reaction using 3a as a substrate was conducted under condition A (Scheme 4b).Consequently, 2a was obtained in 32% yield, indicating that 3a is one of the intermediates in the synthesis of 2a.In contrast, we recovered the starting material 3a under condition B. Furthermore, regarding α,β-unsaturated-γ-alkylidene-γlactam 2 synthesis, we shortened the reaction time to unveil the reaction intermediate, and aminochlorinated product 4a was obtained in a good yield (Scheme 4c).The structure of 4a was confirmed by X-ray crystallographic analysis (for details, see Supplementary Materials).Contrary, the reaction under condition B for 3 h produced only 6% of 4a.Subsequently, the reaction starting from 4a under condition A proceeded smoothly, suggesting that 4a is a possible intermediate for the synthesis of α,β-unsaturated-γ-alkylidene-γ-lactam 2a (Scheme 4d).Additionally, transformation of 4a under condition B also proceeded to afford 2a in good yield.From these results, we assume that the preference for either 2 or 3 is determined by whether aminochlorinated compound 4 is formed in situ.Having studied the scope of the reaction, we next conducted experiments to obtain an insight into the reaction mechanism (Scheme 4).First, under both optimized conditions, the reactions were performed in the presence of the radical scavengers 2,6-di-tert-butyl-4-methylphenol (BHT) or hydroquinone, which led to a significant de- tion B for 3 h produced only 6% of 4a.Subsequently, the reaction starting from 4a under condition A proceeded smoothly, suggesting that 4a is a possible intermediate for the synthesis of α,β-unsaturated-γ-alkylidene-γ-lactam 2a (Scheme 4d).Additionally, transformation of 4a under condition B also proceeded to afford 2a in good yield.From these results, we assume that the preference for either 2 or 3 is determined by whether aminochlorinated compound 4 is formed in situ.Based on these experimental results, a plausible mechanism is proposed for copper-catalyzed intramolecular olefinic C(sp 2 )-H amidation (Scheme 5).For the formation of 5-alkylidene-3-pyrrolin-2-ones 2 under condition A, the nitrogen-centered radical A is initially generated by the Cu II species [43][44][45].It subsequently undergoes addition to an alkene moiety present in the substrate to afford the dibenzylic radical species B. For the next step, there are two possibilities: In the first, B is chlorinated under condition A to Based on these experimental results, a plausible mechanism is proposed for coppercatalyzed intramolecular olefinic C(sp 2 )-H amidation (Scheme 5).For the formation of 5-alkylidene-3-pyrrolin-2-ones 2 under condition A, the nitrogen-centered radical A is initially generated by the Cu II species [43][44][45].It subsequently undergoes addition to an alkene moiety present in the substrate to afford the dibenzylic radical species B. For the next step, there are two possibilities: In the first, B is chlorinated under condition A to form the aminochlorinated product 4a [46][47][48][49], and.subsequent HCl elimination and further oxidation results in the formation of 2a.In the second, 3a is generated by oxidation and deprotonation of B, and further oxidation of 3a occurs to provide 2a [50][51][52].On the other hand, under condition B, 3a is formed via oxidation and deprotonation of B as in condition A, however, no further transformation of 3a occurs, resulting in the formation of 3a as the major product.The detailed mechanism is unclear at present and needs to be clarified through further investigation.
form the aminochlorinated product 4a [46][47][48][49], and.subsequent HCl elimination and further oxidation results in the formation of 2a.In the second, 3a is generated by oxidation and deprotonation of B, and further oxidation of 3a occurs to provide 2a [50][51][52].On the other hand, under condition B, 3a is formed via oxidation and deprotonation of B as in condition A, however, no further transformation of 3a occurs, resulting in the formation of 3a as the major product.The detailed mechanism is unclear at present and needs to be clarified through further investigation.Scheme 5. Plausible mechanism for copper-catalyzed intramolecular dehydrogenative coupling of 1a.

Materials
Materials were purchased from Tokyo Kasei Co. (Tokyo, Japan), Sigma-Aldrich Inc. (St. Louis, MO, USA) and other commercial suppliers, and were used as received.Flash column chromatography was performed with Kanto silica gel 60 N (spherical, neutral, 70-230 mesh).Melting points were measured with a Yazawa micro melting point apparatus and uncorrected.IR spectra were recorded on a SHIMADZU IRAffinity. 1 H NMR spectra were recorded on a JEOL JNMAL400 (400 MHz) spectrometer or a JEOL ECA600 (600 MHz) spectrometer.Chemical shifts are expressed in δ (parts per million, ppm) values and coupling constants are expressed in herts (Hz). 1 H NMR spectra were referenced to tetramethylsilane as an internal standard or to a solvent signal (CDCl3: 7.26 ppm, DMSO-d6: 2.49 ppm). 13C NMR spectra were referenced to a solvent signal (CDCl3: 77.0 ppm, DMSO-d6: 39.5 ppm). 19F NMR spectra were referenced to 4-fluorotoluene as an internal standard (−118.0ppm).The following abbreviations are used: s = singlet, d = Scheme 5. Plausible mechanism for copper-catalyzed intramolecular dehydrogenative coupling of 1a.

Materials
Materials were purchased from Tokyo Kasei Co. (Tokyo, Japan), Sigma-Aldrich Inc. (St. Louis, MO, USA) and other commercial suppliers, and were used as received.Flash column chromatography was performed with Kanto silica gel 60 N (spherical, neutral, 70-230 mesh).Melting points were measured with a Yazawa micro melting point apparatus and uncorrected.IR spectra were recorded on a SHIMADZU IRAffinity. 1 H NMR spectra were recorded on a JEOL JNMAL400 (400 MHz) spectrometer or a JEOL ECA600 (600 MHz) spectrometer.Chemical shifts are expressed in δ (parts per million, ppm) values and coupling constants are expressed in herts (Hz). 1 H NMR spectra were referenced to tetramethylsilane as an internal standard or to a solvent signal (CDCl 3 : 7.26 ppm, DMSO-d 6 : 2.49 ppm). 13C NMR spectra were referenced to a solvent signal (CDCl 3 : 77.0 ppm, DMSO-d 6 : 39.5 ppm). 19F NMR spectra were referenced to 4-fluorotoluene as an internal standard (−118.0ppm).The following abbreviations are used: s = singlet, d = doublet, t = triplet, q = quartet, dd, = double doublet, m = multiplet, and br.s.= broad singlet.Low-and high-resolution mass spectra (LRMS and HRMS) were obtained from Mass Spectrometry Resource, Graduate School of Pharmaceutical Sciences, Tohoku University, on a JEOL JMS-DX 303 and JMS700/JMS-T 100 GC spectrometer.The Bruker D8 VENTURE X-ray diffractometer was used to determine the structure of the grown crystals.

Table 1 .
Effect of reaction parameters a .

Table 1 .
Effect of reaction parameters a .